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June 2020

Consulting For Pharma

Mitochondrial Uncoupling: If You Want to Live Longer, Look to the Skies

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Over the years an enormous amount of both scientific and pseudo-scientific speculation has been aimed at explaining prevailing trends in the lifespan of animals,and how we might apply those lessons to humans.

Since clear, observable trends exist with respect to various groups of animals and lifespan, if we can understand the underlying processes behind those trends, we might be able to extend and maximize our own lifespans.  The most obvious trend is body size versus lifespan, which is robust and repeatable, yet has some outliers that offer tantalizing grounds for speculation.

Figure 1 shows the trend between size and lifespan.  The trend lines, both of which have significant scatter, clearly show two trends, with the data broken down to illustrate the difference between flying and non-flying species.  The striking difference between species who can and cannot fly will be immediately available to anyone who has ever kept a parrot – some species can reliably outlive their human owners.

sizeA number of theories exist to explain the differences between these groupings – and why bats and birds live so much longer.  The authors of the study behind Figure 1 [1] point to the differences in predation vulnerability and argue that flying reduces predation and vulnerability to food shortages.  In that respect, flight offers some of the same advantages as large body size, resulting in the anomalously longer lifespans enjoyed by bats and birds.  The only problem with this hypothesis is that a Malthusian distribution should ensue, and when these populations explode to the very limits of their ecological carrying capacity, one would expect that these advantages would be nullified.  Yet the differences persist.

An alternative view is that animals adapted for flight have a chemical advantage related to flying.  Their tissues express larger quantities of mitochondrial uncoupling proteins, which allow the “leak” of H+ without producing ATP in the mitochondria.  This means that they can “throw away” excess energy produced when they are at rest, necessary because their cellular machinery is designed to process huge amounts of energy during periods of flight.  Tossing the protons made by oxidative respiration has the side benefit that reactive oxygen species (ROS) are destroyed, preventing cellular damage that accumulates over time and causes aging.  Birds therefore age slowly and maintain their youthful function throughout the vast majority of their years.

Other animals, including humans, might be able to benefit from research that targets these proteins.  A growing body of research aimed at treating obesity has a similar goal, and gene therapies that are aimed at stimulating “brown fat” promise to kill two birds with one stone.   Brown fat, a vascular active form of adipose tissue, burns fats rapidly in the presence of oxygen and uncoupling proteins to generate heat.  This is the fat that allows long-lived walruses and cetaceans to keep warm even with wet skin in freezing climates by using fat as nothing more than fuel for the furnace.  Through gene regulation to stimulate brown fat we might be able to reduce obesity and inflammation caused by ROS.

Current research is promising, with the side benefits that gene therapies that increase the activity of the brown fat also cause marked increase in muscle mass and strength, at least in lab mice[2][3].  Scientists at Virginia Tech have recently identified a small mitochondrial uncoupler, named BAM15, that decreases the body fat mass of mice without affecting food intake and muscle mass or increasing body temperature. The research of Santos and colleagues, published in Nature Communications on May 14, 2020, are especially promising for the treatment of obesity and diseases characterized by inflammation.

Although research on mitochondrial decoupling proteins is ongoing, recent progress is promising, and the implications for medicine are sky-high.

[1] Healy, et. al.  2014  Ecology and mode-of-life explain lifespan variation in birds and mammals.  Proc. Royal Soc. B.  DOI: https://doi.org/10.1098/rspb.2014.0298 or visit https://royalsocietypublishing.org/doi/10.1098/rspb.2014.0298.

[2] Weintraub, Arlene.  2020 Gene therapy cuts fat and builds muscle in sedentary mice on unhealthy diets.  Fierce Biotech. May 11. https://www.fiercebiotech.com/research/gene-therapy-cuts-fat-and-builds-muscle-sedentary-mice-unhealthy-diets.

[3] Tang et. al. 2020  Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet–induced obesity.   Science Adv. 08 May 2020:Vol. 6, no. 19. DOI: 10.1126/sciadv.aaz7492 or https://advances.sciencemag.org/content/6/19/eaaz7492.

[4]  https://www.sciencedaily.com/releases/2020/06/200608132539.htm?utm_content=131524119&utm_medium=social&utm_source=twitter&hss_channel=tw-463200485

Will Big Pharma Sabotage its’ Own Re-Shoring?

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The need to reshore American products has been recognized on a federal level for many decades, with legislation such as the original Buy American Act, dated to 1933.

The urgency has grown in recent years, with the burgeoning dependence of the United States on foreign medicines and medical equipment now constituting a huge strategic burden.  The issue has recently come to forefront because of  renewed distrust in supply chain stability thanks to Covid-19, however, and current legislation is upping the ante by including Big Pharma among the list of key players that need to be reformed.

The imperative to return American products home is primarily being addressed through legislation offering incentives aimed at making American businesses more competitive, imposing tariffs on foreign goods and offering tax benefits for American manufacturers.  Although 28% of registered worldwide pharmaceutical API manufacturing sites are located within the US, according to government statistics when we consider the sourcing of raw materials, various estimates suggest that the true foreign dependence is even higher.  Indeed, it is surprisingly difficult for consumers to determine the origin of their drugs and medicines, and many pharmaceutical companies are reticent about their suppliers given the proprietary nature of the information.

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President Trump’s proposed “Buy America” Executive Order, spearheaded by White House trade adviser Peter Navarro, was sidelined by the National Security Council before it could be signed last Friday.  Although the exact details of the order are under negotiation, it is clear that the future of the pharmaceutical industry is at a major crossroads: what happens when the order is signed will shape the manufacturing of pharmaceuticals worldwide.

While this situation underscores the necessity for re-shoring American manufacturing of pharmaceuticals, the biggest opposition to the movement is coming from pharmaceutical lobbyists on Capitol Hill.  Perhaps this is unsurprising, given the enormous disruptions that changing the system would cause, and the fact that many of the losers would be large, powerful corporations with pronounced sourcing from overseas.  Nevertheless, the Pharmaceutical Research and Manufacturers of America (PhRMA), which is the largest pharma lobbying group present, has proffered an argument that re-shoring proposals will “… not only overestimate the potential feasibility and underestimate the time and effort it would take to make such changes, but also misunderstand that a diverse pharmaceutical supply chain is precisely what enables the industry to respond quickly and make adjustments in its supply chain sourcing during natural emergencies and global public health crises.”

Some of this rhetoric is true:  the process will definitely be expensive and difficult.  Some of this is false: parallel supply chains increases the robustness of the worldwide supply.  In fact, redundancy is a key element to airplane safety, and by analogy, it’s plain to see that parallel sources are far more secure than relying on a potentially distant source in an emergency.  This resistance is troubling, since the truth is staring us in the face:  global supply chains are not always reliable.  Imports from China for critical medicines and pharmaceuticals are being cut off entirely due to Covid-19.  This dependence has placed lives at risk since 90 percent of the generic medications that Americans use daily are imported.

The reluctance of  Big Pharma to reduce an unhealthy and greedy dependence on cheap labor and materials will have serious consequences for American healthcare as well as national security.  China’s dominance of the pharma supply chain is highly dangerous to the United States.  Pharmaceutical production must be reshored and even expanded in order to develop secure and safe supply chains for medications, vaccines and medical devices. This crossroads brings us to a critical question: will the United States commit its financial might to developing American pharmaceutical manufacturing capabilities, or will pharma itself stand in the way?